Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
  • C07D295/182—Radicals derived from carboxylic acids
  • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/12—Ketones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/275—Nitriles; Isonitriles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
  • C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Definitions

• the invention relates to pharmaceutical products which contain 7-diphenylmethylenebicycloheptanes and -enes, and the use of these compounds as medicaments, especially for the treatment of hyperlipidemias.
• the invention also relates to new 7-diphenylmethylenebicycloheptanes and 7-diphenylmethylenebicycloheptenes and a process for the preparation thereof.
• German Patent Application DE-A 3,410,498.4 (corresponds to EP-A 0,158,144 and U.S. Pat. No. 4,647,575) relates to these compounds.
• 7-diphenylmethylenebicycloheptane and -heptene derivatives which are not imidazole-substituted likewise have a very strong hypolipidemic action.
• the active compounds take the form of 7-diphenylmethylenebicycloheptanes and -heptenes which are substituted in the 2 position by oxygen- or nitrogen-containing functional groups.
• the invention relates to pharmaceutical products containing a 7-diphenylmethylenebicycloheptane or -heptene of the general formula I ##STR3## in which A is a single or double bond,
• B is a carboxamide group of the formula ##STR4## or a methyleneamino group of the formula ##STR5## in which R 5 and R 6 are identical or different and denote hydrogen or C 1 -C 4 -alkyl, or in which R 5 and R 6 form, together with the nitrogen atom, a morpholine or piperazine ring, or a piperazine ring which is substituted in the 4-position by C 1 -C 4 -alkyl, or B is --OH, --CN, --CO 2 H, --CO 2 -(C 1 -C 4 )-alkyl or ##STR6##
• R 1 is hydrogen, chlorine, C 1 -C 4 -alkyl or, together with B, is an oxime group ( ⁇ N--OH) or oxygen bonded by a double bond ( ⁇ O),
• R 2 is hydrogen or, together with B, is a dicarboxylic anhydride ##STR7## or a dicarboximide ##STR8##
• R 3 and R 4 are identical or different and denote hydrogen, halogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, trifluoromethyl, hydroxyl, amino, (C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino,
• the invention also relates to the use of the compounds of the formula I as medicaments, in particular as hypolipidemics, and the use for the preparation of medicaments.
• alkyl and alkoxy radicals are straight-chain or branched.
• Preferred as active substances are compounds of the formula I in which
• A denotes a single bond
• B denotes a --CO 2 H, --CH, --CH 2 OH or --OH group
• R 1 denotes hydrogen or, together with B, denotes oxygen which is bonded via a double bond ( ⁇ O), or the oxime group ( ⁇ N--OH),
• R 2 denotes hydrogen
• R 3 and R 4 denote hydrogen or halogen.
• the invention also relates to new 7-diphenylmethylene-bicycloheptanes and 7-diphenylmethylenebicycloheptenes of the formula Ia ##STR9## in which A is a single or double bond,
• B is a carboxamide group of the formula ##STR10## or a methyleneamino group of the formula ##STR11## in which r 5 and R 6 are identical or different and denote hydrogen or C 1 -C 4 -alkyl, or in which R 5 and R 6 form, together with the nitrogen atom, a morpholine or piperazine ring, or a piperazine ring which is substituted in the 4 position by C 1 -C 4 -alkyl,
• R 1 is hydrogen or chlorine or, together with B, is an oxime group ( ⁇ N--OH),
• R 2 represents hydrogen
• R 3 and R 4 are identical or different and denote hydrogen, halogen, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, trifluoromethyl, hydroxyl, amino, (C 1 -C 4 )-alkylamino or di-(C 1 -C 4 )-alkylamino,
• the invention also relates to processes for the preparation of compounds of the formula Ia, which comprise
• chlorinating agents examples include thionyl chloride or phosgene.
• A represents a double bond
• this can be hydrogenated by methods known per se, for example with 5% platinum on charcoal. It is expedient in the preparation of compounds of the formula Ia by process A to hydrogenate the bicycloheptenecarboxylic acid to give the bicycloheptanecarboxylic acid.
• the resulting bicycloheptanecarboxylic acid is then converted in a manner known per se, for example in a one-pot reaction with thionyl chloride, into the corresponding acid chloride, and the latter is then reacted with amine to give the carboxamide.
• ketones of the formula Ic which are employed as starting compounds in process B either are described in the literature (cf. for example, Synthesis 1985, 798 and EP-A 0,158,144) or can be prepared in analogy to the described methods.
• reaction with hydroxylamine hydrochloride is preferably carried out in the presence of potassium carbonate in ethanol as solvent.
• acid addition salts from the amines of the general formula Ia are all acids which form physiologically tolerated salts. These include both inorganic acids such as, for example, hydrochloric acid, nitric acid and sulfuric acid, and mono- and bifunctional organic acids, especially carboxylic acids such as acetic acid, succinic acid, tartaric acid etc.
• the compounds of the formula I have valuable pharmacological properties, in particular they exhibit a very strong and beneficial effect on serum lipoproteins.
• the invention relates to pharmaceutical products based on these compounds, and to the use thereof, in particular for affecting serum lipoproteins.
• hyperlipoproteinemias represent a considerable risk factor for the development of arteriosclerotic vascular lesions, especially of coronary heart disease. Hence, it is extremely important to lower elevated serum lipoproteins for the prophylaxis and regression of arteriosclerotic lesions.
• very particular classes of serum lipoproteins are important in this, because the low density (LDL) and very low density (VLDL) lipoproteins represent an atherogenic risk factor whereas the high density lipoproteins (HDL) function as protectives against arteriosclerotic vascular lesions.
• hypolipidemics ought to lower VLDL-cholesterol and LDL-cholesterol in the serum while, where possible, leaving unaffected the HDL-chloresterol concentration, so that the antiatherogenic index ##EQU1## does not fall below 1 by comparison with normal controls.
• the compounds of the formula I have valuable therapeutic properties. Thus, they lower, in particular, the concentration of LDL and VLDL but lower the HDL fraction only in excessive dosage which is sufficient to reduce the LDL-cholesterol concentrations by more than about 50%, so that the result is a great reduction in the LDL fraction without affecting the HDL fraction in the therapeutically utilizable range.
• these compounds represent a considerable advance from the comparison compound clofibrate which, besides LDL, always brings about a very great reduction in HDL, as is evident from the data described hereinafter
• the compounds of the formula I can be used for the prophylaxis and regression of arteriosclerotic lesions, in that they eliminate a casual risk factor.
• the cholesterol contained in the lipoprotein fractions isolated in the ultracentrifuge was determined completely enzymatically by the CHOD-PAP method using the Boehringer-Mannheim assay kit, and the values were converted into ⁇ g/ml of serum.
• the percentage change of the lipoprotein cholesterol in the treated group compared with a control group included in the study under identical conditions is indicated in Table I which is included.
• the minimum dose for hypolipidemic activity is of approximately the same order of magnitude as that for the uterotrophic action.
• Particularly suitable therapeutic formulations of the compounds of the formula I are tablets, coated tablets, capsules, suppositories and syrups.
• the new compounds can be used either alone or mixed with pharmacologically acceptable vehicles.
• a form for oral use is preferred.
• the active compounds are preferably mixed with auxiliaries known per se and converted by methods known per se into suitable dosage forms, such as tablets, hard gelatin capsules, aqueous or oily suspensions or aqueous or oily solutions.
• suitable dosage forms such as tablets, hard gelatin capsules, aqueous or oily suspensions or aqueous or oily solutions.
• suitable dosage forms such as tablets, hard gelatin capsules, aqueous or oily suspensions or aqueous or oily solutions.
• inert vehicles which can be used are magnesium carbonate, lactose or corn starch, with the addition of other substances such as, for example, magnesium stearate.
• the formulation can be carried out as dry or wet granules.
• Particularly suitable oily vehicles or solvents are vegetable and animal oils such as, for example, sunflower oil or fish liver oil.
• a suitable daily dose is about 1 mg to 200 mg, preferably 2 mg to 20 mg, and when the compound of Example 22 is used, 0.5-5 mg, preferably 0.8-2 mg.
• a dosage unit preferably contains 0.5 to 2 mg of active substance of Example 22.
• the formulations can, apart from the customary fillers and vehicles, also contain an antihypertensive such as, for example, a saluretic, reserpine, hydralazine, guanethidine, ⁇ -methyldopa, clonidine, ACE inhibitor or a ⁇ -sympatholytic, a compound having antithrombotic activity, such as, for example, acetylsalicylic acid, sulfinpyrazone, triclopidine and heparinoids, or an agent having antihyperuricemic activity, and oral antidiabetic, a geriatric agent or an agent acting to increase blood flow.
• an antihypertensive such as, for example, a saluretic, reserpine, hydralazine, guanethidine, ⁇ -methyldopa, clonidine, ACE inhibitor or a ⁇ -sympatholytic
• a compound having antithrombotic activity such as
• Tablets suitable for oral administration and containing the ingredients specified hereinafter are prepared in a manner known per se by granulating the active substances and auxiliaries and then compressing the mixture to form tablets. These tablets are suitable for hypolipidemic treatment in a dose of one to two tablets 1-4 times a day.
• Capsules suitable for oral administration contain the ingredients specified hereinafter and can be prepared in a manner known per se by mixing the active substances and auxiliaries and dispensing the mixture into gelatin capasules. These capsules are used for hypolipidemic treatment in a dose of one to two capsules 1-4 times a day.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
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• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
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• Diabetes (AREA)
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• Urology & Nephrology (AREA)
• Heart & Thoracic Surgery (AREA)
• Cardiology (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Furan Compounds (AREA)
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Citations (2)

• 1987
  • 1987-09-23 DE DE19873731913 patent/DE3731913A1/de not_active Withdrawn
• 1988
  • 1988-09-17 EP EP88115289A patent/EP0308839A3/de not_active Withdrawn
  • 1988-09-20 IL IL87818A patent/IL87818A0/xx unknown
  • 1988-09-21 FI FI884343A patent/FI884343A7/fi not_active Application Discontinuation
  • 1988-09-21 US US07/247,968 patent/US5141937A/en not_active Expired - Fee Related
  • 1988-09-21 ZA ZA887047A patent/ZA887047B/xx unknown
  • 1988-09-22 NO NO88884207A patent/NO884207L/no unknown
  • 1988-09-22 DK DK527388A patent/DK527388A/da not_active Application Discontinuation
  • 1988-09-22 KR KR1019880012236A patent/KR890005041A/ko not_active Withdrawn
  • 1988-09-22 JP JP63236657A patent/JPH01113351A/ja active Pending
  • 1988-09-22 PT PT88572A patent/PT88572B/pt not_active IP Right Cessation
  • 1988-09-23 HU HU902054A patent/HU204431B/hu not_active IP Right Cessation
  • 1988-09-23 HU HU884993A patent/HU200991B/hu not_active IP Right Cessation
  • 1988-09-23 AU AU22730/88A patent/AU612177B2/en not_active Ceased

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